Is CFH p.Pro440Ser (c.1318C>T) pathogenic?

CFH p.Pro440Ser (c.1318C>T) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.4045); Very rare (popmax 8.48e-05%, nfe); Associated with basal laminar drusen.

What condition is associated with CFH p.Pro440Ser (c.1318C>T)?

CFH p.Pro440Ser (c.1318C>T) is associated with basal laminar drusen (ClinVar).

How common is CFH p.Pro440Ser (c.1318C>T) in the general population?

CFH p.Pro440Ser (c.1318C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CFH p.Pro440Ser (c.1318C>T)?

AlphaMissense predicts ambiguous (score 0.4045) — an in-silico prediction, not a clinical call.

CFH p.Pro440Ser

c.1318C>T · VCV4976848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4045 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

basal laminar drusen

Computational evidence

Protein change
AlphaMissense	0.4045	ambiguous
REVEL	0.352	indeterminate
SaProt	LLR -11.84	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.99, phastCons 0.029
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,576 alleles

Overall 6.84e-05% 1/1,461,158 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CFH
Protein: p.Pro440Ser
Coding: c.1318C>T
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196690221 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 440: a disulfide bond; the sushi 7 domain

Full CFH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

basal laminar drusen — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFH p.Pro440Arg Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.350+1G>T Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg232Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfh-p-pro440ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown